Asthma is one of the most common chronic diseases in the United States, affecting approximately one in 12 people. Over the previous award period, research by our Projects and Cores identified mucosal mechanisms underlying airway inflammation and remodeling of asthma. Our overarching goal in this renewal of the Program is to uncover the fundamental mechanisms by which airway epithelial cells acquire pro-inflammatory functions and airway smooth muscle cells take on a hypercontractile and remodeling phenotype so that we can apply the discoveries to develop more effective and targeted therapies for asthma patients. We hypothesize that the mucosal epithelial-smooth muscle coupled unit initiates and perpetuates airway inflammation, hyper-reactivity and remodeling. To test this hypothesis, our team of scientists has strategized innovative and mechanistic Projects that are supported by powerful Cores that use cutting-edge technology to study primary airway cells, organotypic cultures, precision cut lung slices, murine genetic models and clinical study of asthma patients. Project 1 is a continuation and investigates how the activation of arginine metabolism, through arginase and nitric oxide (NO) synthases, regulates airway epithelial cell metabolism and epithelial cell cytokine and mucus production. Project 2 is a continuation and proposes to identify the mechanisms by which [[airway epithelium and smooth muscle interactions]] lead to a pathologic hyaluronan matrix in asthma. Developed as a collaborative new project, Project 3 investigates the mechanisms by which NO controls hemeprotein maturation important to airway epithelial function and smooth muscle reactivity, e.g. soluble guanylate cyclase, and [[explores pharmacologic soluble guanylate cyclase activators as a new pathway for bronchodilation.]] Project 4 is a new project made possible by Program-supported collaborations and investigates the resensitization of -adrenergic receptors in the asthmatic airway through kinase pathways that are regulated by nitrosylation. Asthma phenotyping and clinical samples are made available by Core B. Technically challenging and specialized assays for NO and primary cell cultures are supported by a new Core C. Models of asthma using genetically modified mice are provided by Core D. Our investigators have well-established productive collaborations and capitalize on Program synergies and interactions that assure the Program success. The focus of our integrated multidisciplinary team at every step of the Program is to apply discoveries for the better and safer care of asthmatic patients in the very near future.